Nanoliposome C6‐Ceramide in combination with anti‐CTLA4 antibody improves anti‐tumor immunity in hepatocellular cancer

Abstract

Combination therapy represents an effective therapeutic approach to overcome hepatocellular cancer (HCC) resistance to immune checkpoint blockade (ICB). Based upon previous work demonstrating that nanoliposome C6‐ceramide (LipC6) not only induces HCC apoptosis but also prevents HCC‐induced immune tolerance, we now investigate the potential of LipC6 in combination with ICB in HCC treatment. We generated orthotopic HCC‐bearing mice, which have typical features in common with human patients, and then treated them with LipC6 in combination with the antibodies (Abs) for programmed cell death protein 1 (PD‐1) or cytotoxic T‐lymphocyte antigen 4 (CTLA4). The tumor growth was monitored by magnetic resonance imaging (MRI) and the intrahepatic immune profiles were checked by flow cytometry in response to the treatments. Realtime PCR (qPCR) was used to detect the expression of target genes. The results show that LipC6 in combination with anti‐CTLA4 Ab, but not anti‐PD‐1 Ab, significantly slowed tumor growth, enhanced tumor‐infiltrating CD8+ T cells, and suppressed tumor‐resident CD4+CD25+FoxP3+ Tregs. Further molecular investigation indicates that the combinational treatment suppressed transcriptional factor Krüppel‐like Factor 2 (KLF2), forkhead box protein P3 (FoxP3), and CTLA4. Our studies suggest that LipC6 in combination with anti‐CTLA4 Ab represents a novel therapeutic approach with significant potential in activating anti‐HCC immune response and suppressing HCC growth.

C6 Ceramide Inhibits Canine Mammary Cancer Growth and Metastasis by Targeting EGR3 through JAK1/STAT3 Signaling

“…There is a subject of controversy regarding the growth inhibition of C6 ceramide in cancer cells through the apoptotic pathway. Several studies have discovered C6 ceramide-induced apoptosis by evaluating cleaved caspase 3 and/or PARP, such as those on hepatocellular cancer [21], cutaneous T cell lymphoma [22], and pancreatic cancer [23]. On the contrary, studies on head and neck squamous cell carcinoma, melanoma, and breast cancer have revealed that the proliferative inhibitory effect of C6 ceramide is not associated with apoptosis [24,25].…”

Cancer Immunotherapy and Delivery System: An Update

“…For example, pegylated poly (lactic-co-glycolic acid) (PLGA) NPs encapsulating a combined heparanase T cell epitope alone or in combination with TLR3 and TLR7 ligands can be combined with an anti-DEC-205 (CD205) antibody to target DCs [194]. A study in our lab also showed that LipC6, in combination with an anti-CTLA4 antibody, significantly inhibited HCC growth by increasing the infiltration of CD8 T cells [195].…”

The key role of sphingolipid metabolism in cancer: New therapeutic targets, diagnostic and prognostic values, and anti-tumor immunotherapy resistance

“…The dysregulation of sphingolipid metabolism is also frequently associated with cancer stem cells ( 103 , 104 ) and consequently generates a series of tumor immune-related effects; this situation suggests that ceramide is a key player in cancer immunotherapy ( 104 ). Elevated levels of ceramides induce cancer cell death ( 105 ), enhance the host protective immune response, and induce cancer regression ( 101 , 106 ). Elevated levels of S1P induce an increase in the antiapoptotic proteins Bcl-2 and Bcl-XL in macrophages and the M2-type polarization of macrophages, which can also recruit immune cells to immune tissues for immune action ( 107 , 108 ).…”